Review Article

Hepatic

Micheal Tadros1, Faripour Forouhar2 and George Y. Wu1

1Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, CT, USA; 2Department of Anatomic Pathology, University of Connecticut Health Center, Farmington, CT, USA

Abstract ethnicities,6 with an age peak of 20–40 years.6 A second age peak (.50 years) has also been described.6 Sarcoidosis is a multisystem disease characterized by the The hallmark of sarcoidosis is the formation of epithelioid presence of non-caseating granulomas in affected organs. granulomas that are typically non-caseating, in the absence Pulmonary involvement is the most common site of disease of tuberculosis, fungal infection, malignancy, or other causes activity. However, hepatic involvement is also common in of granulomatous reactions.7 The pulmonary system is the sarcoidosis, occurring in up to 70% of patients. Most patients most common site of involvement, and is affected in about with liver involvement are asymptomatic. Therefore, the 90% of cases.6 Extra-thoracic sarcoidosis occurs in 40–50% majority of cases are discovered incidentally, frequently by of patients.8 Sites affected include peripheral lymph nodes the finding of elevated liver enzymes. Pain in the right upper (30%), the hepatic system, the spleen, stomach, small quadrant of the abdomen, fatigue, pruritus, and jaundice may bowel, bone, and skin. Involvement of the solid organs can be associated with liver involvement. Portal hypertension and present as organ enlargement. Dermatological sarcoidosis cirrhosis are complications linked to long-standing hepatic may present as erythema nodosum or lupus pernio. sarcoidosis. Liver biopsy is usually required to confirm the Myopathy, , granulomatous meningitis, facial nerve diagnosis. It is important to differentiate hepatic sarcoidosis palsy, cardiomyopathy, and parotid enlargement have been from other autoimmune and granulomatous liver diseases. reported less commonly. Not all cases of hepatic sarcoidosis require treatment. For There are two classic syndromes described for sarcoidosis. symptomatic patients, the first line treatment includes The first is Lo¨fgren syndrome, which is characterized by hilar or ursodeoxycholic acid. Various immunosup- lymphadenopathy, erythema nodosum, arthritis and .6 pressant agents can be used as second line agents. Rarely, The second is Heerfordton syndrome, which is characterized severe cases require liver transplantation. by uveitis, swelling of the , fever, and facial E 2013 The Second Affiliated Hospital of Chongqing Medical palsy.9 University. Published by XIA & HE Publishing Ltd. All rights The pathogenesis of sarcoidosis is still not completely reserved. understood, but it is thought to be multifactorial, involving the interplay of immunological, genetic, and environmental Introduction factors.1,6 It has been theorized that an environmental trigger initiates a specific immune reaction in a genetically Sarcoidosis is an inflammatory disorder of unknown etiology predisposed individual. The immunological response in sar- categorized by the presence of non-caseating granulomas, coidosis includes T helper 1 (Th1) cells triggered by an which can involve multiple organs of the body,1 in the antigen, leading to cytokine production, mainly tumor absence of infections, other autoimmune diseases, and necrosis factor alpha10 which in turn, leads to macrophage exposure to foreign agents. It has been estimated that the aggregation with subsequent granuloma formation.11 Certain worldwide prevalence of sarcoidosis is 2–60 per 100,000 histocompatibility antigens have been associated with sar- people.2 Sarcoidosis affects all ethnicities with higher pre- coidosis such as human leukocyte antigen-A1 (HLA-A1), B8, valence rates described in patients of Scandinavian descent.2 DRB1, DQB1, and DRB3.12 This suggests a genetic suscept- In contrast, sarcoidosis has been only rarely reported in ibility and familial clustering of the disease. Some of the patients of Chinese and Taiwanese origin.3,4 In the USA, possible postulated triggers of environmental antigens African Americans have been reported to have a three times include reactive oxygen species, and viruses (herpes simplex higher age-adjusted incidence of the disease.1,5 Sarcoidosis virus, cytomegalovirus, retroviruses) and bacteria (Borrelia affects females more often than males across all ages and burgdorferi, mycobacteria).2,6

Keywords: Sarcoid; Granuloma; Epitheloid. Epidemiology of hepatic sarcoidosis Abbreviations: ACE, serum angiotensin converting enzyme; AFB, acid-fast bacteria; AMA, anti-mitochondrial antibody; ERCP, endoscopic retrograde cho- In biopsy and autopsy studies of patients with systemic langiopancreatography; MRCP, magnetic resonance cholangiopancreatography; sarcoidosis, liver involvement was found in about 50–80%,17 MRI, magnetic resonance imaging; p-ANCA, peripheral anti-neutrophil cytoplas- mic antibody; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. whereas only 10–30% of patients presented with abnormal 2,18 Received: 21 September 2013; Revised: 9 October 2013; Accepted: 9 October liver enzymes during laboratory testing. The majority of 2013 q patients with hepatic sarcoidosis are asymptomatic, despite DOI of original article: 10.14218/JCTH.2013.00016. the presence of granulomas on biopsy, abnormal liver Correspondence to: George Y. Wu, Department of Medicine, Division of 14 Gastroenterology-Hepatology, University of Connecticut Health Center, enzymes, or radiological evidence of disease. It has been Farmington, CT 06030, USA. E-mail: [email protected] reported that the percentage of patients with clinically

Journal of Clinical and Translational Hepatology 2013 vol. 1 | 87–93 Tadros M. et al: Sarcoid of the liver significant disease is less than 20%.19 Risk factors associated transplantation cases in the USA. Unfortunately, they often with hepatic sarcoidosis include African American ethnicity, have a worse prognosis than patients with other cholestastic prior exposure to pegylated interferon, and the presence of liver diseases such as primary biliary cirrhosis and primary splenomegaly.13,14,20 Reports on the differences in preva- sclerosingcholangitis.29 Some case reports have linked sar- lence based on gender have been contradictory. In studies coidosis with an increased risk of developing Budd-Chiari30 containing hundreds of patients, one study reported liver syndrome, hepatopulmonary syndrome,28 hepatocellular disease to be more common in women,21 whereas the other carcinoma,31,32 and biliary sarcoid mimicking cholangiocarci- showed the opposite.22 noma. Table 1 lists postulated mechanisms of liver injury in hepatic sarcoidosis. Table 2 summarizes the clinical spectrum Spectrum of hepatic sarcoidosis of the disease.

There is a spectrum of clinical presentations of liver involve- Investigations ment in sarcoidosis. Of the more than 50% of patients who have hepatic granulomas on liver biopsy, only 10–30% have Elevations of alkaline phosphatase and/or gamma glutamyl- elevated serum liver enzymes.2,18 About 20% of patients transpeptidase have been correlated with cholestasis and have palpable hepatomegaly or splenomegaly. Radiological liver involvement.25,34 Alkaline phosphatase of hepatobiliary examination (ultrasound or computed tomography) is accu- origin can be elevated 5–10 times the upper limit of normal. rate in the detection of organomegaly, demonstrating this Aminotransferase elevations are usually mild and less fre- feature in about 40% of cases.13,17 However, even in cases of quent compared with elevations in alkaline phosphatase.19 elevated serum liver enzymes or radiological abnormalities, The severity of liver test abnormalities was shown to be evidence of organ dysfunction is rare. associated with the extent of granulomatous inflammation.33 Some clinical symptoms and signs suggest liver involve- Hyperglobulinema may be seen. Measurement of the serum ment, and may warrant a liver biopsy. Systemic symptoms angiotensin converting enzyme (ACE) levels can be useful; such as fatigue, fever, and arthralgias are non-specific, but they have been reported to be elevated in about 60% of are present in the majority of patients with active liver patients with active sarcoidosis.35–37 However, the test lacks sarcoidosis.23,24 More specific symptoms include jaundice sensitivity and specificity, with low positive and negative and pruritus, mostly from chronic cholestasis.25,26 Right predictive values (84 and 74%, respectively).38 Normal levels upper quadrant abdominal pain, in theory, results from can be seen in chronic forms and in patients who have been stretching of the Glisson’s capsule by hepatomegaly as a on corticosteroids. Therefore, a normal ACE level does not consequence of the increasing intrahepatic volume occupied rule out sarcoidosis, but an elevated level may help distin- by the developing hepatic granulomas. Abdominal pain has guish sarcoidosis from other granulomatous disease. been reported to occur in 15% of patients with sarcoidosis, Elevated ACE levels can also be present in patients with and jaundice in less than 5%.19 inflammatory bowel disease.36 Long-standing disease has been reported to result in Radiological studies39 such as ultrasonography,40 com- portal hypertension in 3–18% of patients.16 This may be due puted tomography (CT)41 or magnetic resonance imaging initially to compression of portal venules by granulomas, and (MRI)42,43 may show hepatomegaly or multiple hypointense can result in variceal bleeding. A small proportion (6–8%) of or hypoattenuated liver nodules. The occurrence of such patients can develop portal hypertension because of progres- multiple nodules can be confused with liver metastasis or sion to cirrhosis. Indeed, some patients can develop end- other granulomatous diseases. The presence of concomitant stage liver disease and require liver transplantation.26–28 splenic granulomas may help point towards a diagnosis of These account for about 0.012% of the total number of liver sarcoidosis.

Table 1. Postulated mechanisms of liver injury in hepatic sarcoidosis

Liver injury Possible mechanism Jaundice13,14 Chronic cholestasis from hepatic fibrosis, bile duct strictures (mimics cholangiocarcinoma) Obstruction of small bile ductules External compression from a sarcoid mass at the pancreatic head, or porta-hepatis adenopathy Hepatocellular carcinoma Cirrhosis13,15 Granuloma formation with subsequent hepatic fibrosis, with or without granulomatous phlebitis and thrombosis Secondary biliary cirrhosis Portal hypertension16,17 Intrahepatic pre-sinusoidal obstruction secondary to granulomas or sinusoidal obstruction from biliary fibrosis or cirrhosis Pre-hepatic obstruction from portal vein thrombosis Post-hepatic (hepatic vein thrombosis); Budd-Chiari syndrome Portal hypertension can occur without cirrhosis Ascites17 Cirrhosis and portal hypertension Cor pulmonale Hypoalbuminemia Peritoneal sarcoidosis Chylous ascites (sarcoid lymphadenopathy)

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Table 2. The clinical spectrum of hepatic sarcoidosis17,19,33

Feature Presentation (%) Asymptomatic 50–80% Abnormal liver profile 30% 10–15% patients are symptomatic, and 85% are symptomatic. Organomegaly (Liver or spleen) 50% detected on radiological exam, , 15–20% detected clinically Clinical hepatitis Abdominal pain 15%, pruritus and jaundice , 5% Cirrhosis 6–8% Portal hypertension 3–18% Liver failure requiring liver transplantation 0.012% of all liver transplants in the USA

Liver biopsy should be considered if the diagnosis is granulomas from drug reaction, and predispose patients to uncertain and treatment is considered. Some authors recom- develop opportunistic infections that can cause liver granu- mend obtaining a liver biopsy if aminotransferase levels are lomas.7,46,47 In cases of sarcoidosis co-existing with hepatitis elevated at least two-fold above the upper limit of normal. C, granulomas may be due to hepatitis C, or may have been Histopathological examination is the definitive diagnostic induced by prior exposure to interferon therapy for hepatitis tool. In sarcoidosis, granulomas are usually abundant and C.48 well-formed in the periportal and the portal regions. Typically, the granulomas are non-caseating and epithelioid (Fig. 1). Management There is scant lymphocytic inflammatory infiltration. Occasionally, fibrinoid necrosis, prominent fibrosis, and When evaluating patients with hepatic sarcoidosis for treat- multinucleated giant cells can be seen. Staining for acid-fast ment, consultation with other specialists involved in the mycobacteria, and for fungi should be negative. Progression patient’s care is recommended to ensure that other organ 27 of the disease can result in micronodular cirrhosis. systems that may be involved with sarcoidosis such as the pulmonary system, central nervous system and/or ocular Differential diagnosis systems are treated adequately.49

Hepatic sarcoidosis needs to be differentiated from other Observation without medical management (autoimmune) liver diseases, especially primary biliary 44,45 cirrhosis and primary sclerosing cholangitis (Table 3). Observation alone is indicated for patients with asymptomatic The differential diagnosis of granulomatous liver disease liver disease or mild elevations of serum liver enzymes, and can be separated into four main categories based on the type normal synthetic liver function without evidence of choles- 7 of granulomas present: epithelioid, foreign body, lipogranu- tasis.17,19,49 Hepatomegaly alone noted on physical exam- lomatous, and lymphohistiocytic. Sarcoid epithelioid granu- ination and/or radiographic investigation in the absence of lomas are characterized by macrophages that aggregate to symptoms does not qualify as an indication for treatment. It form giant cells surrounded by fibrin rings. Table 4 includes has been noted that in some asymptomatic patients, some of these etiologies, and their differentiating character- abnormal serum liver tests can resolve spontaneously or istics. In the setting of post-transplant granulomas, it is remain stable for many years.25,34 important to remember that the treatment itself can lead to Medical treatment

For patients who have symptoms of liver involvement, and have biochemical evidence of cholestasis or who are at high risk for developing hepatic complications, pharmacological therapy should be considered.17,19,49 The first line agents that have been studied include corticosteroids and urso- deoxycholic acid.

Steroids

It has been shown that corticosteroids can decrease the number of hepatic granulomas by suppression of the inflam- matory response,50 and reduce liver size25 which may be helpful for patients with persistent abdominal pain due to hepatomegaly. In addition, steroids are recommended for patients with constitutional symptoms such as fever, fatigue, pruritus, and weight loss. Low-dose prednisone (10–20 mg/ Fig. 1. A liver biopsy specimen showing a single portal epithelioid daily) may be sufficient for those with mild symptoms, while a granuloma (arrow) surrounded by a thin cuff of lymphocytes. H&E, 6100. higher dose of prednisone (20–40 mg/daily) is warranted for

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Fig. 2. A liver biopsy specimen showing: a, a conglomerate of granulomatous reaction (arrow) with significant fibrosis (arrow head); b, significant as well conglomerate of epithelioid granulomas with giant cells (arrow), but without necrosis. Trichrome, 6400.

those with severe symptoms.17,51 Prednisone can also be considered for patients with significant adenopathy in the porta hepatis. Treatment duration should be determined by clinical and laboratory response. Some authors recommend 12 months of therapy before tapering the dose.52 Relapsing symptoms may require long-term therapy or steroid-sparing agents. Side effects of long-term steroid use (including ostopenia, bone fractures, avascular hip necrosis, hyperglycemia, cataracts, and hypertension) should be considered.52 No studies have reported on the use of oral budesonide (a systemic steroid eliminated on first pass through the liver) in the treatment of hepatic sarcoidosis. The benefit of steroids in patients at the extremes of the clinical spectrum (that is, asymptomatic individuals or patients with cirrhosis and portal hypertension) is question- able. Steroids can help in the normalization of these laboratory abnormalities in asymptomatic patients 14,34 Fig. 3. A liver biopsy specimen showing a sarcoid granuloma in liver with with elevated aminotransferases. However, it is impor- central fibrinoid necrosis (arrow). H&E, 6400. tant to consider that serum liver tests can normalize

Table 3. List of features that distinguish hepatic sarcoid from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)

PBC Sarcoidosis PSC44

Histology Granulomas - usually few, Granulomas: many, well-formed Concentric prominent periductal fibrosis: poorly defined and and usually periportal. ‘‘onion skin’’ fibrosis. No granulomas. located in the portal tract Prominent fibrosis and along damaged bile ducts, multi-nucleated giant cells. with eosinophils. Less prominent biliary injury. Florid ductal lesions present in early disease Serum Tests Anti-mitochondrial Serum angiotensin converting Peripheral anti-neutrophil cytoplasmic antibody (AMA) enzyme (ACE) antibody (p-ANCA) Imaging — — Magnetic resonance cholangiopancreato- graphy (MRCP), endoscopic retrograde cholangiopancreatography (ERCP): generalized beading of the biliary tree Extra-hepatic Rare Pulmonary nodules, hilar Ulcerative colitis disease lymphadenopathy

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Table 4. List of features of various granulomatous liver diseases (adapted from Coash et al.7)

Mycobacterium tuberculosis Acid-fast bacteria (AFB) inside epithelioid granulomas and giant cells, often with a ring of lymphocytes and histiocytes M aviumin tracellulare Aggregates of foamy macrophages in parenchyma and portal triads with positive AFB staining M leprae Foamy histiocytes in portal tracts and lobules with multiple AFB found Brucella Non-caseating granulomas Rickettsia Fibrin rings surrounding vesicles of fat Francisella Suppurative microabscesses with surrounding macrophages Listeria Microabscesses with small granulomas Bartonella henselae Stellate abscesses with three distinct zones Tropheryma whipplei Epithelioid granulomas Histoplasma Macrophages and lymphocytes with histoplasma and epithelioid cells in the center Schistosoma Eosinophils with fibrosis and collagen deposition in peri-portal and peri-sinusoidal areas, often with eggs in the center Leishmania Fibrin ring or epithelioid granulomas Hepatitis C Epithelioid granulomas Drugs and chemicals Granulomas with eosinophils Malignancy Non-necrotic granulomas

spontaneously.25,34 Because there is a lack of long-term Treatment of advanced liver disease studies, it is unclear if steroids prevent liver damage or halt the progression of the disease. In patients with progressive Portal hypertension and decompensated cirrhosis should be disease (significant fibrosis, chronic cholestasis, and portal managed by standard measures. Steroids may not be hypertension), steroid treatment has not been shown to have beneficial, and liver transplantation may be required. beneficial effects.16 Reported rates of graft and patient survival for hepatic sarcoidosis are 78% at 1 year, 66–67% at 3 years, and 60– 29 Ursodeoxycholic acid 61% at 5 years. Recurrence of disease in the graft has been reported.58 Ursodeoxycholic acid decreases biliary secretion of cholic and chenodeoxycholic acid, and inhibits the intestinal absorption Prognosis of bile salt. It also helps to modulate the immune response by decreasing HLA class I and class II antigens on the cell The mortality rate of sarcoidosis is about 1–5%.59,60 Death membranes of the hepatic and bile duct epithelial cells, usually occurs from severe pulmonary, cardiac, and central respectively.53 Recent studies have shown a beneficial effect nervous system disease rather than hepatic involvement. of this agent in the treatment of hepatic sarcoidosis, These survival rates are comparable to other causes of especially when patients with cholestasis are symptomatic transplantation, except for PBC and PSC.29,61,62 with pruritus.49 It has the potential effect of delaying the progression of the disease. Given its relative safety compared Conclusions to steroids, some authors recommend starting with urso- deoxycholic acid before prednisone. In a recent retrospective Hepatic sarcoidosis is a granulomatous disease of unknown study of 17 patients comparing placebo vs. prednisone vs. 54 etiology. Around 70% of patients have epithelioid non-case- ursodeoxycholic acid, ursodeoxycholic acid was found to be ating granulomas on liver biopsy; 20–40% of patients have superior in improving aminotransferase levels, pruritus, and 54 55 hepatomegaly or elevated liver enzymes. Most of the cases fatigue. The usual dose is 13–15 mg/kg orally per day. with liver involvement are asymptomatic and do not require treatment. Pain in the right upper quadrant of the abdomen, Second-line and third-line agents fatigue, pruritus, and jaundice are the most commonly associated symptoms. For symptomatic patients, prednisone These agents may be useful for patients for whom prednisone and/or ursodeoxcholic acid may be considered. Those fails or patients who are deemed to be steroid dependent. patients who do not respond to steroids and/or ursodeox- Azathioprine has been reported to normalize aminotrans- cholic acid may require other immunosuppressive agents. ferases, but can also cause acute hepatitis.49 Methotrexate, Portal hypertension and cirrhosis are possible complications glutathione, chlorambucil, cyclosporine, cyclophosphamide, from long-standing hepatic sarcoidosis. Patients may require thalidomide, pentoxifylline, and infliximab56,57 have been liver transplantation, but disease recurrence in the graft has reported to be beneficial. However, there is inadequate been reported, and survival rates tend to be lower than those evidence to support the use of these agents.49 for patients transplanted for other diseases.

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Conflict of interest [26] Blich M, Edoute Y. Clinical manifestations of sarcoid liver disease. J Gastroenterol Hepatol 2004;19:732–737. [27] Malhotra A, Naniwadekar A, Sood G. Hepatobiliary and pancreatic: None Cirrhosis secondary to hepatic sarcoidosis. J Gastroenterol Hepatol 2008; 23:1942. [28] Gupta S, Faughnan ME, Prud’homme GJ, Hwang DM, Munoz DG, Kopplin P. Author contributions Sarcoidosis complicated by cirrhosis and hepatopulmonary syndrome. Can Respir J 2008;15:124–126. Writing the medical text (MT), writing the pathology section [29] Vanatta JM, Modanlou KA, Dean AG, Nezakatgoo N, Campos L, Nair S et al. (FF), organizing and editing the manuscript (GYW). Outcomes of orthotopic liver transplantation for hepatic sarcoidosis: An analysis of the United Network for organ sharing/organ Procurement and Transplantation Network data files for a comparative study with cholestatic Acknowledgments liver diseases. Liver Transpl 2011;17:1027–1034. [30] Deniz K, Ward SC, Rosen A, Grewal P, Xu R. Budd-Chiari syndrome in sarcoidosis involving liver. Liver Int 2008;28:580–581. The support of the Herman Lopata Chair in Hepatitis Research [31] Chalasani P, Vohra M, Sheagren JN. An association of sarcoidosis with (to GYW) is gratefully acknowledged. hepatocellular carcinoma. Ann Oncol 2005;16:1714–1715. [32] Wong VS, Adab N, Youngs GR, Sturgess R. Hepatic sarcoidosis com- plicated by hepatocellular carcinoma. Eur J Gastroenterol Hepatol 1999; References 11:353–355. [33] Cremers J, Drent M, Driessen A, Nieman F, Wijnen P, Baughman R et al. Liver- test abnormalities in sarcoidosis. Eur J Gastroenterol Hepatol 2012;24:17– [1] Culver DA. Sarcoidosis. Immunol Allergy Clin North Am 2012;32:487–511. 24. [2] Baughman RP, Lower EE. Sarcoidosis. Harrison’s Principles of Internal [34] Vatti R, Sharma OP. Course of asymptomatic liver involvement in sarcoi- Medicine 2008:2135–2142. dosis: Role of therapy in selected cases. Sarcoidosis Vasc Diffuse Lung Dis [3] Perng RP, Chen JH, Tsai TT, Hsieh WC. Sarcoidosis among Chinese in Taiwan. 1997;14:73–76. J Formos Med Assoc 1997;96:697–699. [35] Silverstein E, Friedland J, Kitt M, Lyons HA. Increased serum angiotensin [4] Perng RP, Chou KT, Chu H, Chung YM. Familial sarcoidosis in Taiwan. J Formos converting enzyme activity in sarcoidosis. Isr J Med Sci 1977;13:995–1000. Med Assoc 2007;106:499–503. [36] Silverstein E, Fierst SM, Simon MR, Weinstock JV, Friedland J. Angiotensin- [5] Rybicki BA, Major M, Popovich Jr. J, Maliarik MJ, Iannuzzi MC. Racial converting enzyme in Crohn’s disease and ulcerative colitis. Am J Clin Pathol differences in sarcoidosis incidence: A 5-year study in a health maintenance 1981;75:175–178. organization. Am J Epidemiol 1997;145:234–241. [37] Lieberman J. Elevation of serum angiotension converting enzyme (ACE) level [6] Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357: in sarcoidosis. Am J Med 1975;59:365–372. 2153–2165+2108. [38] Studdy PR, Bird R. Serum angiotensin converting enzyme in sarcoidosis - Its [7] Coash M, Forouhar F, Wu CH, Wu GY. Granulomatous liver diseases: A review. value in present clinical practice. Ann Clin Biochem 1989;26:13–18. J Formos Med Assoc 2012;111:3–13. [39] Koyama T, Ueda H, Togashi K, Umeoka S, Kataoka M, Nagai S. Radiologic [8] Belfer MH, Stevens RW. Sarcoidosis: A primary care review. Am Fam Manifestations of Sarcoidosis in Various Organs. Radiographics 2004;24:87– Physician 1998;58:2041–2050. 104. [9] Takahashi N, Horie T. . Nihon Rinsho Jpn J Clin Med 2002; [40] Kessler A, Mitchell DG, Israel HL, Goldberg BB. Hepatic and splenic 60:1822–1826. sarcoidosis: Ultrasound and MR imaging. Abdom Imaging 1993;18:159– [10] Zissel G, Prasse A, Muller-Quernheim J. Immunologic response of sarcoi- 163. dosis. Semin Respir Crit Care Med 2010;31:390–403. [41] Nakata K, Iwata K, Kojima K, Kanai K. Computed tomography of liver [11] Chesnutt MS, Gifford AH, Prendergast TJ. Pulmonary disorders. Current sarcoidosis. J Comput Assist Tomogr 1989;13:707–708. medical diagnosis & treatment 2010. [42] Warshauer DM, Molina PL, Hamman SM, Koehler RE, Paulson EK, Bechtold RE [12] Lazarus A. Sarcoidosis: Epidemiology, Etiology, Pathogenesis, and Genetics. et al. Nodular sarcoidosis of the liver and spleen: Analysis of 32 cases. Dis Mon 2009;55:649–660. Radiology 1995;195:757–762. [13] Judson MA. Hepatic, splenic, and gastrointestinal involvement with sarcoi- [43] Warshauer DM, Semelka RC, Ascher SM. Nodular sarcoidosis of the liver and dosis. Semin Respir Crit Care Med 2002;23:529–541. spleen: appearance on MR images. J Magn Reson Imaging 1994;4:553–557. [14] Kennedy PTF, Zakaria N, Modawi SB, Papadopoulou AM, Murray-Lyon I, Du [44] Alam I, Levenson SD, Ferrell LD, Bass NM. Diffuse intrahepatic biliary Bois RM et al. Natural history of hepatic sarcoidosis and its response to strictures in sarcoidosis resembling sclerosing cholangitis: Case report and treatment. Eur J Gastroenterol Hepatol 2006;18:721–726. review of the literature. Dig Dis Sci 1997;42:1295–1301. [15] Moreno-Merlo F, Wanless IR, Shimamatsu K, Sherman M, Greig P, Chiasson [45] Rudzki C, Ishak KG, Zimmerman HJ. Chronic intrahepatic cholestasis of D. The role of granulomatous phlebitis and thrombosis in the pathogenesis of sarcoidosis. Am J Med 1975;59:373–387. cirrhosis and portal hypertension in sarcoidosis. Hepatology 1997;26:554– 560. [46] Lagana SM, Moreira RK, Lefkowitch JH. Hepatic Granulomas: Pathogenesis [16] Valla D, Pessegueiro-Miranda H, Degott C, Lebrec D, Rueff B, Benhamou JP. and Differential Diagnosis. Clin Liver Dis 2010;14:605–617. Hepatic sarcoidosis with portal hypertension. A report of seven cases with a [47] Gur C, Lalazar G, Doviner V, Fridlender ZG, Molcho V, Abu-Much S et al. Late- review of the literature. Q J Med 1987;63:531–544. onset sarcoidosis after liver transplantation for primary biliary cirrhosis. [17] Ebert EC, Kierson M, Hagspiel KD. Gastrointestinal and hepatic manifesta- J Clin Gastroenterol 2007;41:329–332. tions of sarcoidosis. Am J Gastroenterol 2008;103:3184–3192. [48] Fiel MI, Shukla D, Saraf N, Xu R, Schiano TD. Development of hepatic [18] Chen ESD, Moller DR. Sarcoidosis. Current Rheumatology Diagnosis and granulomas in patients receiving pegylated interferon therapy for recurrent Treatment 2004. hepatitis C virus post liver transplantation. Transpl Infect Dis 2008;10:184– [19] Dulai PS, Rothstein RI. Disseminated sarcoidosis presenting as granuloma- 189. tous gastritis: A clinical review of the gastrointestinal and hepatic manifesta- [49] Cremers JP, Drent M, Baughman RP, Wijnen PA, Koek GH. Therapeutic tions of sarcoidosis. J Clin Gastroenterol 2012;46:367–374. approach of hepatic sarcoidosis. Curr Opin Pulm Med 2012;18:472–482. [20] Adla M, Downey KK, Ahmad J. Hepatic sarcoidosis associated with pegylated [50] Moller DR. Treatment of sarcoidosis – from a basic science point of view. interferon alfa therapy for chronic hepatitis C: Case report and review of J Intern Med 2003;253:31–40. literature. Dig Dis Sci 2008;53:2810–2812. [51] Rose AS, Tielker MA, Knox KS. Hepatic, Ocular, and Cutaneous Sarcoidosis. [21] Newman LS, Rose CS, Bresnitz EA, Rossman MD, Barnard J, Frederick M et al. Clin Chest Med 2008;29:509–524. A case control etiologic study of sarcoidosis: environmental and occupational [52] MacArthur KL, Forouhar F, Wu GY. Intra-abdominal complications of risk factors. Am J Respir Crit Care Med 2004;170:1324–1330. sarcoidosis. J Formos Med Assoc 2010;109:484–492. [22] Valla DC, Benhamou JP. Hepatic granulomas and hepatic sarcoidosis. Clin [53] Be´cheur H, Dall’osto H, Chatellier G, Charton-Bain M, Aubertin J, Attar A et al. Liver Dis 2000;4:269–85, ix–x. Effect of ursodeoxycholic acid on chronic intrahepatic cholestasis due to [23] Harder H, Bu¨chler MW, Fro¨hlich B, Stro¨bel P, Bergmann F, Neff W et al. sarcoidosis. Dig Dis Sci 1997;42:789–791. Extrapulmonary sarcoidosis of liver and pancreas: A case report and review [54] Bakker GJ, Haan YC, Maillette de Buy Wenniger LJ, Beuers U. Sarcoidosis of of literature. World J Gastroenterol 2007;13:2504–2509. the liver: to treat or not to treat? Neth J Med 2012;70:349–356. [24] Israel HL, Margolis ML, Rose LJ. Hepatic granulomatosis and sarcoidosis - [55] Ayyala US, Padilla ML. Diagnosis and treatment of hepatic sarcoidosis. Curr Further observations. Dig Dis Sci 1984;29:353–356. Treat Options Gastroenterol 2006;9:475–483. [25] Israel HL, Sones M. Sarcoidosis: Clinical observation on one hundred sixty [56] Baughman RP. Methotrexate for sarcoidosis. Sarcoidosis Vasc Dif 1998;15: cases. Arch Intern Med 1958;102:766–776. 147–149.

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[57] Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. [60] Iwai K, Tachibana T, Hosoda Y, Matsui Y. Sarcoidosis autopsies in Japan. Chest 2005;127:1064–1071. Frequency and trend in the last 28 years. Sarcoidosis 1988;5:60–65. [58] Fidler HM, Hadziyannis SJ, Dhillon AP, Sherlock S, Burroughs AK. Recurrent [61] Casavilla FA, Gordon R, Wright HI, Gavaler JS, Starzl TE, Van Thiel DH. hepatic sarcoidosis following liver transplantation. Transplant Proc 1997;29: Clinical course after liver transplantation in patients with sarcoidosis. Ann 2509–2510. Intern Med 1993;118:865–866. [59] Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on sarcoidosis. [62] Barbers RG. Role of transplantation (lung, liver, and heart) in sarcoidosis. Clin Eur Respir J 1999;14:735–737. Chest Med 1997;18:865–874.

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